Ariad’s revised Iclusig manuscript to be published on 7 November in NEJM - sources

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Ariad’s (NASDAQ:ARIA) amended manuscript of chronic myeloid leukemia (CML) agent, Iclusig (ponatinib), in the Phase II PACE trial will be published in the New England Journal of Medicine (NEJM) on 7 November, two sources told BioPharm Insight. The paper was modified to add toxicity and adverse event data after the recent FDA investigation into Iclusig’s cardiovascular (CV) side-effect profile, they noted.

Ariad and the NEJM declined to comment.

In December 2012, the FDA granted Iclusig accelerated approval in CML and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients whose leukemia is resistant or intolerant to standard tyrosine kinase inhibitor (TKI) treatment, or those with the rare but difficult-to-treat T315I mutation. The FDA’s accelerated approval program allows quicker approval of drugs that treat an unmet medical need based on a surrogate endpoint, which is thought to predict clinical benefit. In the case of Iclusig, the accelerated approval was based on response data from the 449-patient Phase II PACE trial (NCT01207440).

The FDA approval came with a boxed warning for blood clots and liver toxicity. At the time of FDA’s decision, Ariad had 11-month patient follow-up data from the PACE study.

On 9 October, the FDA placed a partial clinical hold on patient enrollment in all Iclusig trials after 24-month follow-up PACE trial data indicated an increased rate of serious CV events, according to an Ariad press release. When the PACE data was analyzed for approval, the CV events were not as prominent as they are reported to be now, the first source said. These events are very concerning because they are irreversible, he added. At 24-month follow-up, serious arterial thrombosis -- a dangerous blood clot in an artery -- occurred in 11.8% of patients (versus 8.0% at 11-month follow-up), Ariad’s press release states.

Two days later, the FDA announced an investigation of CV side effects associated with Iclusig. Blood clots or narrowing of blood vessels developed in at least 20% of Iclusig-treated patients in the most recent data submitted to the FDA, an 11 October press release states.

The first draft of the NJEM manuscript had no information about CV events, the second source noted. After trial investigators urged the company to include a section on such events, Ariad wrote two lines addressing these side effects, he added. The NEJM held the paper until more CV data was added, he explained. On 23 October, investigators were alerted that the updated manuscript had been accepted by the NEJM with a publication date of 7 November, the two sources said.

Ariad reported Iclusig sales USD 20.3m in 1H13, after launching in the US in early-2013. Ariad’s shares have dropped over 80% since the FDA clinical hold on October 9.

Best option as refractory agent

Although concerned by the CV side effects, all sources highlighted Iclusig’s extraordinary results in CML or Ph+ ALL patients who have failed several other treatments and have no other options, and in individuals with the T315I mutation, which results in resistance to TKIs.

It is unclear if the FDA will still allow Iclusig’s use in patients who have failed treatment on one TKI, or limit usage to those who have failed two or more TKIs, or have the T315I mutation, the second source said. Patients who fail on their first TKI now have other available options, namely Pfizer’s (NYSE:PFE) Bosulif (bosutinib), noted Dr Amanda Cashen, assistant professor, oncology division, bone marrow transplantation & leukemia section, Washington University School of Medicine, St Louis, Missouri. The FDA may narrow Iclusig’s label, such that only patients who have failed two or more TKIs or have the mutation are eligible, she said.

Ritchie noted the side effects seen in PACE have not been seen in long-term follow-up studies with second-generation TKIs -- Novartis’ (VTX:NOVN) Tasigna (nilotinib) or Bristol-Myers Squibb’s (NYSE:BMY) Sprycel (dasatinib) -- which suggests the adverse events were Iclusig-specific.

The second source referenced CV concerns with other TKIs, particularly Tasgina, adding this is not necessarily a singular problem specific to Iclusig. Tasigna’s FDA approval included a black-box warning for QT prolongation, a heart rate complication.

Newly-diagnosed CML patients treated with Tasigna reported a higher incidence of CV events in the Phase III ENESTnd study, as compared with Novartis’ Gleevec (imatinib), noted EPIC investigator Dr Jeffrey Lipton, head, chronic myeloid leukemia program, Ontario Cancer Institute. It is possible that the PACE trial side effects are not only due to Iclusig, since the majority of the trial’s participants had previously received Tasigna, he said. Some 66% of PACE patients had received prior Tasigna therapy, according to a 2012 presentation.

Front-line CML discussion put to rest

Ariad announced the Phase III EPIC trial of Iclusig in front-line, or previously-untreated, CML had been discontinued on 18 October. Iclusig is no longer viewed as a potential option in front-line CML, sources noted.

Iclusig’s EPIC trial is likely to be limited by potential side effects, a weak comparator drug, a questionable primary endpoint and the inability to compare data versus second-generation TKIs, BioPharm Insight reported on 9 August.

Investigators had informed the company about the frequency of CV events seen in EPIC, but “Ariad was not listening,” the second source said. Investigators had asked Ariad to reduce Iclusig’s 45 milligram (mg) dose in EPIC, but the company did not do so until after the FDA began its investigation, the first and second sources explained.

Dose-reduction options

All sources interviewed agreed the 45mg dose is likely too high. Ariad should compare Iclusig 45mg versus 30mg (or even 15mg) in relapsed/refractory CML patients, said PACE investigator Dr Meir Wetzler, chief, division of leukemia, Roswell Park Cancer Institute, Buffalo, New York. The first source suggested a PACE continuation trial to dose-reduce the patients who did well on Iclusig 45mg down to 30mg.

Ariad has made some dose adjustments, Lipton said, questioning if the dose adjustments would have a meaningful impact. Some patients are staying on the same dose because they have no other options and are doing well on Iclusig, he noted.